Steven M. Brunelli

Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality

Patients receiving hemodialysis have high rates of cardiovascular morbidity and mortality that may be related to the hemodynamic effects of rapid ultrafiltration. Here we tested whether higher dialytic ultrafiltration rates are associated with greater all-cause and cardiovascular mortality, and hospitalization for cardiovascular disease. We used data from the Hemodialysis Study, an almost-7-year randomized clinical trial of 1846 patients receiving thrice-weekly chronic dialysis. The ultrafiltration rates were divided into three categories: up to 10 ml/h/kg, 10-13 ml/h/kg, and over 13 ml/h/kg. Compared to ultrafiltration rates in the lowest group, rates in the highest were significantly associated with increased all-cause and cardiovascular-related mortality with adjusted hazard ratios of 1.59 and 1.71, respectively. Overall, ultrafiltration rates between 10-13 ml/h/kg were not associated with all-cause or cardiovascular mortality; however, they were significantly associated among participants with congestive heart failure. Cubic spline interpolation suggested that the risk of all-cause and cardiovascular mortality began to increase at ultrafiltration rates over 10 ml/h/kg regardless of the status of congestive heart failure. Hence, higher ultrafiltration rates in hemodialysis patients are associated with a greater risk of all-cause and cardiovascular death.

Hemoglobin Variability and Mortality in ESRD

Hemoglobin levels vary substantially over time in hemodialysis patients, and this variability may portend poor outcomes. For a given patient, hemoglobin concentration over time can be described by absolute levels, rate of change, or by the difference between observed level and expected level based on the preceding trend (i.e., seemingly random variability). We investigated the independent associations of these different methods of describing hemoglobin over time with mortality in a retrospective cohort of 34,963 hemodialysis patients. Hemoglobin concentration over time was modeled with linear regression for each subject, and the model was then used to define the subjects absolute level of hemoglobin (intercept), temporal trend in hemoglobin (slope), and hemoglobin variability (residual standard deviation). Survival analyses indicated that each 1g/dl increase in the residual standard deviation was associated with a 33% increase in rate of death, even after adjusting for multiple covariates. Patient characteristics accounted for very little of the variation in our hemoglobin variability metric (R2 = 0.019). We conclude that greater hemoglobin variability is independently associated with higher mortality.

Incidence, Outcomes, and Comparisons across Definitions of AKI in Hospitalized Individuals

BACKGROUND AND OBJECTIVES At least four definitions of AKI have recently been proposed. This study sought to characterize the epidemiology of AKI according to the most recent consensus definition proposed by the Kidney Disease Improving Global Outcomes (KDIGO) Work Group, and to compare it with three other definitions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective cohort study of 31,970 hospitalizations at an academic medical center in 2010. AKI was defined and staged according to KDIGO criteria, the Acute Dialysis Quality Initiatives RIFLE criteria, the Acute Kidney Injury Network (AKIN) criteria, and a definition based on a model of creatinine kinetics (CK). Outcomes of interest were incidence, in-hospital mortality, length of stay, costs, readmission rates, and posthospitalization disposition. RESULTS AKI incidence was highest according to the KDIGO definition (18.3%) followed by the AKIN (16.6%), RIFLE (16.1%), and CK (7.0%) definitions. AKI incidence appeared markedly higher in those with low baseline serum creatinine according to the KDIGO, AKIN, and RIFLE definitions, in which AKI may be defined by a 50% increase over baseline. AKI according to all definitions was associated with a significantly higher risk of death and higher resource utilization. The adjusted odds ratios for in-hospital mortality in those with AKI were highest with the CK definition (5.2; 95% confidence interval [95% CI], 4.1 to 6.6), followed by the RIFLE (2.9; 95% CI, 2.2 to 3.6), KDIGO (2.8; 95% CI, 2.2 to 3.6), and AKIN (2.6; 95% CI, 2.0 to 3.3) definitions. Concordance in diagnosis and staging was high among the KDIGO, AKIN, and RIFLE definitions. CONCLUSIONS The incidence of AKI in hospitalized individuals varies depending on the definition used. AKI according to all definitions is associated with higher in-hospital mortality and resource utilization. AKI may be inappropriately diagnosed in those with low baseline serum creatinine using definitions that incorporate percentage increases over baseline.

Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis

BACKGROUND In the past decade, more than 200 cases of nephrogenic systemic fibrosis (NSF) have been identified, primarily among patients with advanced kidney disease. Multiple studies have suggested an association between gadolinium-based contrast agents (GBCAs) and NSF. We performed a systematic review and meta-analysis to examine this potential association. METHODS A systematic review of studies examining the association between any GBCA and NSF was performed. A search for controlled studies was conducted in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. If controlled data for a GBCA was not available, we searched for case reports and series. Relevant data were extracted and meta-analyses were performed. RESULTS Seven of 144 identified studies met inclusion criteria; gadodiamide was the sole or predominant GBCA in four of these; one study exclusively examined gadopentetate. Other GBCAs were not specifically examined in controlled or uncontrolled studies. Meta-analysis of controlled trials demonstrated a significant association between GBCA exposure and NSF [odds ratio (OR) 26.7; 95% confidence interval (CI) 10.3-69.4] and gadodiamide and NSF (OR 20.0; 95% CI 3.7-107.8). Examination of the evidence using established criteria suggested that this association was causal. CONCLUSIONS The current state of evidence suggests an association and potentially causal link between the use of GBCAs and the development of NSF among patients with advanced kidney disease. Additional study is warranted to clarify the potential association of GBCAs other than gadodiamide with NSF.

Association Between Iodinated Contrast Media Exposure and Incident Hyperthyroidism and Hypothyroidism

BACKGROUND Sudden exposure to high iodide levels may cause thyroid dysfunction. Despite compelling biological plausibility and clinical implication, the association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism has not been rigorously studied. METHODS We performed a nested case-control study of patients treated between January 1, 1990, and June 30, 2010, who did not have preexisting hyperthyroidism or hypothyroidism. In parallel analyses, incident hyperthyroid or hypothyroid cases were defined by a change in thyrotropin level from normal (at baseline) to low or high (follow-up measurement). Euthyroid controls were selected using an incidence density sampling approach and were matched to cases on the basis of age, sex, race/ethnicity, estimated glomerular filtration rate, follow-up thyrotropin measurement date, and interval between baseline and the follow-up thyrotropin measurement date. Iodinated contrast media exposure was assessed using claims data for contrast-enhanced computed tomography or cardiac catheterization. RESULTS In total, 178 and 213 incident hyperthyroid and hypothyroid cases, respectively, were matched to 655 and 779 euthyroid controls, respectively. Iodinated contrast media exposure was associated with incident hyperthyroidism (odds ratio [OR], 1.98; 95% CI, 1.08-3.60), but a statistically significant association with incident hypothyroidism was not observed (OR, 1.58; 95% CI, 0.95-2.62). In prespecified secondary analysis, iodinated contrast media exposure was associated with incident overt hyperthyroidism (follow-up thyrotropin level ≤ 0.1 mIU/L; OR, 2.50; 95% CI, 1.06-5.93) and with incident overt hypothyroidism (follow-up thyrotropin level >10 mIU/L; OR, 3.05; 95% CI, 1.07-8.72). CONCLUSION Iodinated contrast media exposure is associated with subsequent development of incident hyperthyroidism and incident overt hypothyroidism.

Association of Mortality Risk with Various Definitions of Intradialytic Hypotension

Intradialytic hypotension is a serious and frequent complication of hemodialysis; however, there is no evidence-based consensus definition of intradialytic hypotension. As a result, coherent evaluation of the effects of intradialytic hypotension is difficult. We analyzed data from 1409 patients in the HEMO Study and 10,392 patients from a single large dialysis organization to investigate the associations of commonly used intradialytic hypotension definitions and mortality. Intradialytic hypotension definitions were selected a priori on the basis of literature review. For each definition, patients were characterized as having intradialytic hypotension if they met the corresponding definition in at least 30% of baseline exposure period treatments or characterized as control otherwise. Overall and within subgroups of patients with predialysis systolic BP<120 or 120-159 mmHg, an absolute nadir systolic BP<90 mmHg was most potently associated with mortality. Within the subgroup of patients with predialysis BP≥160 mmHg, nadir BP<100 mmHg was most potently associated with mortality. Intradialytic hypotension definitions that considered symptoms, interventions, and decreases in BP during dialysis were not associated with outcome, and when added to nadir BP, symptom and intervention criteria did not accentuate associations with mortality. Our results suggest that nadir-based definitions best capture the association between intradialytic hypotension and mortality.

Intradialytic Hypotension and Risk of Cardiovascular Disease

BACKGROUND AND OBJECTIVES Patients undergoing hemodialysis have an elevated risk of cardiovascular disease-related morbidity and mortality compared with the general population. Intradialytic hypotension (IDH) is estimated to occur during 20%-30% of hemodialysis sessions. To date, no large studies have examined whether IDH is associated with cardiovascular outcomes. This study determined the prevalence of IDH according to interdialytic weight gain (IDWG) and studied the association between IDH and outcomes for cardiovascular events and mortality to better understand its role. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study retrospectively examined records of 39,497 hemodialysis patients during 2007 and 2008. US Renal Data System claims and dialysis provider data were used to determine outcomes. IDH was defined by current Kidney Disease Outcomes Quality Initiative guidelines (≥20 mmHg fall in systolic BP from predialysis to nadir intradialytic levels plus ≥2 responsive measures [dialysis stopped, saline administered, etc.]). IDWG was measured absolutely (in kilograms) and relatively (in percentages). RESULTS IDH occurred in 31.1% of patients during the 90-day exposure assessment period. At baseline, the higher the IDWG (relative or absolute), the greater the frequency of IDH (P<0.001). For all-cause mortality, the median follow-up was 398 days (interquartile range, 231-602 days). Compared with patients without IDH, IDH was associated with all-cause mortality (7646 events; adjusted hazard ratio, 1.07 [95% confidence interval, 1.01 to 1.14]), myocardial infarction (2396 events; 1.20 [1.10 to 1.31]), hospitalization for heart failure/volume overload (8896 events; 1.13 [1.08 to 1.18]), composite hospitalization for heart failure/volume overload or cardiovascular mortality (10,805 events; 1.12 [1.08 to 1.17]), major adverse cardiac events (MACEs; myocardial infarction, stroke, cardiovascular mortality) (4994 events, 1.10 [1.03 to 1.17]), and MACEs+ (MACEs plus arrhythmia or hospitalization for heart failure/volume overload) (12,221 events; 1.14 [1.09 to 1.19]). CONCLUSIONS IDH was potently associated with cardiovascular morbidity and mortality. Clinical trials to ascertain causality are needed and should consider reduction in IDWG as a potential means to reduce IDH.

Sodium Thiosulfate Therapy for Calcific Uremic Arteriolopathy

BACKGROUND AND OBJECTIVE Calcific uremic arteriolopathy (CUA) is an often fatal condition with no effective treatment. Multiple case reports and case series have described intravenous sodium thiosulfate (STS) administration in CUA, but no studies have systematically evaluated this treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study included 172 patients undergoing maintenance hemodialysis who had CUA and were treated with STS between August 2006 and June 2009 at Fresenius Medical Care North America. Of these, 85% completed STS therapy. Clinical, laboratory, and mortality data were abstracted from clinical information systems. Responses to survey questionnaires sent to treating physicians regarding patient-level outcomes were available for 53 patients. Effect on CUA lesions and mortality were summarized as CUA outcomes. Relevant laboratory measures, weight (using pairwise comparisons of values before, during, and after STS), and adverse events were summarized as safety parameters. RESULTS Mean age of the cohort was 55 years, and 74% of patients were women. Median STS dose was 25 g, and median number of doses was 38. Among surveyed patients, CUA completely resolved in 26.4%, markedly improved in 18.9%, improved in 28.3%, and did not improve in 5.7%; in the remaining patients (20.8%), the response was unknown. One-year mortality in patients treated with STS was 35%. Adverse events, laboratory abnormalities, and weight-related changes were mild. Significant reductions in serum phosphorous (P=0.02) and parathyroid hormone (P=0.01) were noted during STS treatment in patients who completed the therapy. CONCLUSIONS Although conclusive evidence regarding its efficacy is lacking, a majority of patients who received STS demonstrated clinical improvement in this study.

Prescribed dietary phosphate restriction and survival among hemodialysis patients.

BACKGROUND AND OBJECTIVES Hyperphosphatemia is common among hemodialysis patients. Although prescribed dietary phosphate restriction is a recommended therapy, little is known about the long-term effects on survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a post hoc analysis of data from the Hemodialysis Study (n = 1751). Prescribed dietary phosphate was recorded at baseline and annually thereafter. Marginal structural proportional hazard models were fit to estimate the adjusted association between dietary phosphate restriction and mortality in the setting of time-dependent confounding. RESULTS At baseline, prescribed daily phosphate was restricted to levels ≤ 870, 871 to 999, 1000, 1001 to 2000 mg, and not restricted in 300, 314, 307, 297, and 533 participants, respectively. More restrictive prescribed dietary phosphate was associated with poorer indices of nutritional status on baseline analyses and a persistently greater need for nutritional supplementation but not longitudinal changes in caloric or protein intake. On marginal structural analysis, there was a stepwise trend toward greater survival with more liberal phosphate prescription, which reached statistical significance among subjects prescribed 1001 to 2000 mg/d and those with no specified phosphate restriction: hazard ratios (95% CIs) 0.73 (0.54 to 0.97) and 0.71 (0.55 to 0.92), respectively. Subgroup analysis suggested a more pronounced survival benefit of liberal dietary phosphate prescription among nonblacks, participants without hyperphosphatemia, and those not receiving activated vitamin D. CONCLUSIONS Prescribed dietary phosphate restriction is not associated with improved survival among prevalent hemodialysis patients, and increased level of restriction may be associated with greater mortality particularly in some subgroups.

History-Adjusted Marginal Structural Analysis of the Association between Hemoglobin Variability and Mortality among Chronic Hemodialysis Patients

BACKGROUND AND OBJECTIVES Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin. RESULTS In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively. CONCLUSIONS Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.